The organ of Corti is a sensory specialization of the mammalian cochlea that mediates our sense of hearing. Understanding how the organ of Corti develops may shed light on the basis of certain inherited forms of deafness. It may also help attempts to regenerate the sensory cells of the cochlea in individuals where these cells have been destroyed - a common condition known as sensorineural hearing loss. The organ of Corti derives from a prosensory domain of cells running the length of the embryonic cochlear duct, but the nature of the molecular signals that induce this domain are controversial. Several studies suggest that the Notch signaling pathway induces the prosensory domain, but our own preliminary experiments using mice defective in Notch signaling do not support this idea. Instead, we suggest that Bone Morphogenetic Protein (BMP) signaling induces the prosensory domain and may also induce the non-sensory regions on either side of the organ of Corti in a concentration-dependent fashion. We do not rule out a role for Notch signaling in the developing cochlea however, as our data suggest that Notch signaling may define the boundaries of the organ of Corti by interacting with the Fringe family of Notch-modifying enzymes. The goals of this proposal are to identify the signals that induce the prosensory domain and the organ of Corti, and that correctly impart patterning information to the cochlear duct so that the right cell types are formed in the right place at the right time. We will accomplish our goals with three different approaches. First, we will use two different strains of genetically engineered mice in which the Notch signaling pathway is defective to determine whether the prosensory domain and the organ of Corti develop correctly without Notch signals. Second, we will use mice in which the BMP signaling pathway is defective, and examine the development of the cochlea. We will also test whether exposing pieces of embryonic cochlea to different concentrations of BMP can induce different cochlear cell types to differentiate. Finally, we will use genetically engineered mice that we believe will be unable to form a normal boundary between the organ of Corti and surrounding parts of the cochlea to examine the importance of this boundary in normal organ of Corti development. PUBLIC HEALTH RELEVANCE: This proposal aims to understand how the cochlea develops in mammals. Since the cochlea is responsible for human hearing, we believe that our work will help us understand the basis of some forms of hereditary hearing loss. It may also suggest ways to re-grow damaged parts of the cochlea in individuals who have lost their hearing.